This invention relates to the diagnosis and/or treatment of a patient""s heart and particularly to the delivery of therapeutic or diagnostic devices and agents to a patient""s heart tissue from within the patient""s heart chamber.
Coronary artery disease affects the lives of millions of patients worldwide. Many therapies are available for atherosclerosis, including CABG surgery to bypass blocked arteries, PTCA interventions to attempt to restore patency, stents that also attempt to maintain patency, atherectomy to remove the collected plaque, and a number of pharmacological approaches that attempt to reduce the effects of narrowing of vessel lumens, by the stenosis, by reducing the amount of plaque or by altering the hemodynamic characteristics of the patient""s blood. While the aforesaid procedures provide well known clinical improvements, none provide a fully satisfactory long term therapy. The presently available pharmacological therapies are of limited value. Ideally, a non-invasive pharmacological or genetic therapy would facilitate reperfusion of the ischemic myocardium, either by restoring patency, or by creating new blood vessels to supply the ischemic region with additional oxygenated blood.
A number of different substances and techniques are known for attempting to treat coronary artery disease by the administration of a therapeutic substance to a patient. One common method of administration is systemic administration. For example, EPO Application EP 314105 discloses the oral administration or intramuscular injection of an xe2x80x9cangiogenesis enhancer.xe2x80x9d U.S. Pat. No. 5,480,975 discloses treating hypoxic tissue damage by local or topical administration of a transition metal compound to induce VEGF expression, either by local administration or topical application. The indirect nature of these routes of administration are generally less desirable and not universally applicable to all forms of substances that might be used to treat ischemic myocardium.
Using a catheterization procedure to deliver a substance to the vessels in the vicinity of the stenosis is also known. For example, PCT Application WO 9723256 discloses the percutaneous delivery of an angiogenic factor to a vessel wall through the lumen of a catheter. The distal end of the catheter is provided with infusion ports that engage the vessel wall when the catheter is expanded, and infusion may be enhanced by providing needles or other penetrating elements. U.S. Pat. No. 5,681,278 discloses treating vascular thrombosis and angioplasty restenosis by administering a bioactive agent to an extravascular treatment site, particularly introducing such an agent proximally adjacent to the exterior of a coronary artery. U.S. Pat. No. 5,698,531 discloses site specific installation of cells or the transformation of cells by delivering proteins by catheterization to discrete blood vessel segments wherein the agent is situated on the walls of the blood vessel or perfused in the tissue of the vessel. U.S. Pat. No. 5,523,092 discloses an indwelling catheter for localized delivery of a substance into a tissue conduit without disrupting the fluid flow. U.S. Pat. No. 5,244,460 discloses the intracoronary arterial delivery of a blood vessel growth promoting peptide periodically over several days. None of these references, however, address the provision of a substance directly into the myocardial tissue.
Recent advances in biotechnology have shown great promise for treating coronary artery disease. In Circulation 1998, 97:645-650, Schumacher et al. report treating coronary heart diseases using human growth factor FGF-I (basic fibroblast growth factor) to induce neoangiogenesis in ischemic myocardium. The FGF-I was administered during a CABG procedure by injection into the myocardium distal to the IMA/LAD anastamosis and close to the LAD. The results reported demonstrate the efficacy of FGF-I treatment. However, administration by direct injection during surgery is less than optimal because it is as invasive to the patient as a CABG procedure. In addition, at least one fibroblast growth factor has also been delivered using a microparticle carrier delivered to an artery via a catheter in a non-ischemic model, as reported in Nature Biotechnology 1998; 16:134 and 159-160. The intra-arterial delivery of microparticles produced positive results, but was chosen so that the surrounding tissue would be undamaged. The article indicates that non-invasive techniques to deliver genes into peripheral ischemic myocardium tissue are presently unavailable.
Targeted delivery of therapeutic or diagnostic devices and/or agents is a desirable but often difficult task. For therapeutic and diagnostic devices the advantages include shorter and less traumatic procedures and for therapeutic and diagnostic agents the benefits include more efficient use of the agent and the limitation of the agent action to a desired region. Whether the delivery of a therapeutic or diagnostic device to a desired region of a patient""s heart tissue from within the heart chamber thereof is successful and efficient is frequently the result of the physician""s skill which can vary considerably from physician to physician and from day to day with the same physician. Accurate delivery of various substances to the tissue of a patient""s heart wall can be a function of the same physician skill. Additionally, successful and effective substance delivery can also be a function of minimizing systemic loss, keeping the substance within the desired region, timing and ensuring a sufficient quantity of substance in the desired area for sufficient period of time to achieve the desired therapeutic or diagnostic effect.
U.S. Pat. No. 5,840,049, filed on Jun. 7, 1995, entitled THERAPEUTIC AND DIAGNOSTIC AGENT DELIVERY, describes a method and system for delivering a therapeutic or diagnostic agent by first forming a channel in a heart wall from within a heart chamber defined by the wall and then delivering or depositing the agent within the channel. Reference is made to the use of a laser to form the channel, particularly in conjunction with a transmyocardial revascularization procedure. U.S. Pat. No. 5,840,049 is hereby incorporated herein by reference in its entirety. Agents described in U.S. Pat. No. 5,840,049 include vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (aFGF, bFGF), angiogenin, nitric oxide, prostaglandin, prostaglandin synthase and other prostaglandin synthetic enzymes and isoforms of superoxide dismutase and other antioxidant proteins.
Coronary artery disease is also successfully treated by transmyocardial revascularization (TMR) alone, using methods and apparatus such as those disclosed in U.S. Pat. Nos. 5,380316, 5,389,096 and 5,54,152, all of which are incorporated herein by reference. Using intraoperative, minimally invasive or percutaneous techniques, energy is delivered directly to the myocardium in the ischemic area and as a result, a focal injury occurs. This focal injury is typically in the form of a small xe2x80x9cchannelxe2x80x9d formed by a laser. It is believed that the focal injury acts to stimulate subsequent neovasculogenesis. Moreover, in addition to the reperfusion of the ischemic region, there is evidence that the disruption of certain afferent nerves in the tissue and other effects provides acute and chronic reduction in angina pain.
Suitable means for creating a site for angiogenesis were referenced in copending application Ser. No. 08/976,831, filed on Nov. 24, 1997 (Aita et al.), which is incorporated herein in its entirety. The application describes an intravascular system for myocardial revascularization which is introduced percutaneously into a peripheral artery and advanced through the patient""s arterial system into the left ventricle of the patient""s heart. The procedure affects only the endocardium and the myocardium from within the left ventricle. This procedure eliminates the need of the prior intraoperative procedures to open the chest cavity and to penetrate through the entire heart wall in order to form the channel through the endocardium into the myocardium.
While the percutaneous method and system for introducing therapeutic and diagnostic agents into a patient""s heart wall as described in U.S. Pat. No. 5,840,049 represented a substantial advance, one of the difficulties with the procedure was that it was difficult to ensure delivery of all of the agent into the channel and keeping the agent within the channel for a sufficient period until the desired therapeutic or diagnostic affect occurred.
Thus, there exists a long felt, yet unmet need for methods and apparatus that permit the localized introduction of a substance into the myocardium directly, either during an intraoperative procedure or percutaneously. It would also be desireable to have an improved apparatus and improved techniques that will permit the adjunctive delivery of substances into localized areas within the myocardium efficaciously, efficiently and in a manner that can enjoy widespread adoption by cardiac surgeons and interventional cardiologists. What has also been needed is an improved delivery system and method for delivering a therapeutic or diagnostic device or agent into heart tissue from within the patient""s heart chamber, particularly to provide access to all or substantially all of the endocardial surface from within the heart chamber for delivery of such agents and devices.
The present invention is directed to a system for delivering an elongated therapeutic or diagnostic device or agent into the wall of a patient""s heart from within a chamber defined by the heart wall. The system of the invention has the capability to access tissue in the endocardial, myocardial, and epicardial layers of the heart wall, in addition to other areas of the heart. The invention provides access to a wide region of the patient""s endocardial lining and the tissue beneath it. The system also accurately places and effectively holds the distal end of the system at one or more desired locations within the patient""s heart chamber at a desired orientation, e.g. perpendicular or near perpendicular, with respect to the patient""s endocardium. The perpendicular or near perpendicular orientation of the distal extremity of the cannula or other device with respect to the endocardial surface of the heart chamber is most desirable. As used herein the terms xe2x80x9cnormalxe2x80x9d and xe2x80x9cperpendicularxe2x80x9d shall include variations of up to 30xc2x0 from a normal or perpendicular orientation.
The delivery catheter system of the invention generally includes a first guiding or delivery catheter which has a relatively straight main shaft section and a shaped distal shaft section which is configured to have a discharge axis selected so that it is generally aligned with or parallel to the longitudinal axis of the patient""s left ventricle. The discharge axis is herein defined to be the longitudinal axis of the most distal segment of the catheter described. The system also generally includes a second guiding or delivery catheter slidably and rotatably disposed within an inner lumen of the first delivery catheter and provided with a shaped distal section configured to have a discharge axis with a desired orientation.
The system of the invention also has substance delivery member for delivery of a therapeutic or diagnostic agent which is disposed within the inner lumen of the second delivery catheter. The substance delivery member is configured so it can be advanced into the wall of the patient""s heart. The member preferably has an injector, which may be a syringe or other suitable device, provided on the proximal end of a cannula to deliver the diagnostic or therapeutic agent in a carrier fluid or gel or in solid form through the inner lumen of the cannula into the tissue of the patient heart wall.
Preferably, the distal extremity of the substance delivery member which extends out the distal end of the second delivery catheter has sufficient rigidity to penetrate the tissue of the heart, and be self-supporting within the environment of the heart chamber. Generally, the distal portion of the substance delivery member is considered as being xe2x80x9cself supportingxe2x80x9d if a force of at least 4 grams, preferably at least 8 grams, is required to deflect the free end of a cantilevered specimen 0.5 inch (12.7 mm) in length (span length) of cannula a distance of one millimeter. A sheath surrounding the cannula can also act to provide support.
In one preferred embodiment, an injector or syringe member containing a therapeutic or diagnostic agent is incorporated into the distal extremity of an elongated cannula slidably disposed within the inner lumen of the second delivery catheter for delivery of the agent into the heart wall. The agent may be in a carrier fluid or gel, or may be in a solid form. The injector is actuated at the proximal end of the delivery system which extends out of the patient. The injector may be set up for a single or multiple doses.
The location of the distal end of the substance delivery member within the heart chamber, and particularly with respect to the endocardial surface, can be detected fluoroscopically by providing a radiopaque marker on the distal extremity of the delivery member, either or both of the polymer sheath or elongated cannula, and optionally, either or both of the delivery catheters. The radiopaque marker can be made from a suitable metal, such as gold, platinum or tantalum, or the like, or a material such as BaSO4 or Bismuth can be added to the material that forms the polymer sheath, or the first or second delivery catheter. The use of dye injections through a port in the distal end of first or the second delivery catheter may be employed to further facilitate the location of the distal end of these catheters. Other means such as a variety of proximity detectors, including ultrasonic proximity detectors, may be employed to detect contact between the distal end of the substance delivery member or the delivery catheters and the endocardium.
In accordance with one presently preferred embodiment of the present invention, the first delivery catheter has proximal and distal ends, a port in the distal end and an inner lumen extending within the catheter to the port in the distal end. The first delivery catheter has a relatively straight main shaft section and a preshaped distal section configured to point in a direction so that the discharge axis of this catheter is aligned with or parallel or near parallel to the longitudinal axis of the left ventricle or other chamber into which it is inserted. For many applications the first delivery catheter is about 90 to about 130 cm, preferably about 100 to about 120 cm in length.
The first delivery catheter preferably has a main shaft section and a shaped distal section with a first segment and a second segment which provide a discharge axis approximating the longitudinal axis or long dimension of the heart chamber. The first segment of the distal shaft section of the first delivery catheter should be at an angle of about 95xc2x0 to about 160xc2x0, preferably about 100xc2x0 to about 150xc2x0 with respect to a proximally adjacent second segment of the distal shaft section. The proximally adjacent second segment should be at an angle of about 95xc2x0 to about 160xc2x0, preferably about 100xc2x0 to about 150xc2x0 with respect to either the proximally adjacent main shaft section or a third segment of the distal shaft section proximally adjacent to the second segment. If there is a third segment of the distal section, it is at an angle of about 110xc2x0 to about 170xc2x0, preferably about 120xc2x0 to about 150xc2x0 with respect to proximally adjacent main shaft section. The first and second segments should each be about 0.5 to about 5 cm, preferably about 0.5 to about 4 cm in length, with the total length of the shaped distal section with two segments being about 2 to about 6 cm. If the distal section has a third segment, it should have a length of about 1 to about 5 cm, preferably about 2 to about 4 cm. The length of the shaped distal section with three segments should be about 3 to about 8 cm, preferably about 4 to about 7 cm.
In another embodiment, the shaped distal section of the first delivery catheter has a single angled segment which provides a discharge axis approximating the longitudinal axis or long dimension of the heart or other chamber into which it is disposed. In this embodiment the single angled segment of the distal shaft section has a length of about 2 to about 8 cm, preferably about 4 to about 6 cm and is at an angle of about 95xc2x0 to about 160xc2x0, preferably about 100xc2x0 to about 140xc2x0 with respect to a proximally adjacent portion of the main shaft section.
The second delivery catheter of the invention is longer than the first delivery catheter, and is slidably and preferably rotatably disposed within inner lumen of the first delivery catheter. The second delivery catheter likewise has proximal and distal ends, a port in the distal end and an inner lumen extending within the second delivery catheter to the port in the distal end. The second delivery catheter has a relatively straight main shaft section and a distal section which is at an angle of about 80xc2x0 to about 140xc2x0, preferably about 90xc2x0 to about 120xc2x0 with respect to the main shaft section thereof. The second delivery catheter should be at least 10 cm longer, preferably about 15 to about 50 cm longer, than the first delivery catheter and is about 100 to about 150 cm, preferably about 110 to about 140 cm in length. The shaped distal section of the second delivery catheter should have a radius of curvature of about 2 to 30 mm, preferably about 4 to about 20 mm between the main shaft section and the exit or discharge axis through the port in the distal end of the shaped distal section. The length of the shaped distal section of the second delivery catheter is about 0.5 to about 4 cm, preferably about 1 to about 3 cm. The angles of the various segments of the distal section of the first and second delivery catheters facilitate directing the operative distal end of an elongated substance delivery member, which is slidably disposed within the inner lumen of the second delivery catheter, toward the region of the endocardium where the procedure is to be performed at an orientation that is preferably perpendicular or near perpendicular with the endocardial surface of the patient""s heart wall.
The second delivery catheter is rotatably and slidably disposed within the inner lumen of the first delivery catheter to facilitate the desired placement and orientation of the shaped distal section of the second delivery catheter within the left ventricle, e.g. substantially normal to the endocardium. In this manner an elongated cannula slidably disposed within the inner lumen of the second delivery catheter or the injector at the distal extremity of the second delivery catheter is properly oriented with respect to the endocardial surface of the heart chamber in order to effectively be inserted into the heart wall. The elongated cannula may also be disposed within a polymer sheath which is slidably disposed with in the inner lumen of the second delivery catheter. The polymer sheath has a proximal end and a distal end, preferably with at least one penetration limiter disposed on the distal end of the polymer sheath. The sheath protects the tip from inadvertently damaging tissue or other parts of the catheter delivery system.
The distal sections of the first and second delivery catheters are preferably preformed into a desired shape so that they will provide a desired orientation for the delivery system when they extend into the patient""s heart chamber. However, the catheters may alternatively be provided with control lines, pull wires, or other suitable means (e.g., a shape memory or a superelastic or pseudoelastic NiTi element) to deflect or otherwise shape the distal sections of the catheters once the distal extremity of the delivery system extends into the heart chamber. The system of the present invention essentially provides access at a desired normal or near normal orientation to the entire semi-conical inner surface of the free wall defining part the patient""s heart chamber and the intraventricular septum.
The first and second delivery catheters are preferably relatively stiff catheters so that the position of the cannula or other substance delivery member will be maintained during the procedure even though the heart is beating and blood is flowing within the chamber. The delivery catheters, and particularly the first delivery catheter, are preferably provided with relatively stiff proximal and shaped distal sections with a more flexible intermediate section which is configured to be disposed within the patient""s aortic arch during the procedure as described in copending application Ser. No. 08/813,503 entitled CATHETER WITH FLEXIBLE INTERMEDIATE SECTION and filed on Mar. 7, 1997, which is incorporated herein by reference.
In a presently preferred embodiment of practicing the method of the invention, the first delivery catheter of the delivery catheter system is introduced into a peripheral artery, such as the femoral artery, and advanced through the patient""s arterial system until the distal end of the first catheter is disposed within the patient""s left ventricle. The position of the first delivery catheter is adjusted by the physician under fluoroscopic observation or other techniques until its distal tip is oriented generally along or parallel to the longitudinal axis of the left ventricle. The second delivery catheter is advanced through the previously introduced first delivery catheter which has a distal end appropriately positioned within the left ventricle. The distal end of the second delivery catheter is then adjusted under flouroscopic visualization, or the like, until it is oriented perpendicular to the wall of the heart adjacent the tissue to be treated. The substance delivery member is then advanced distally until contact is made with the tissue of the heart wall. The elongated cannula is then advanced into the tissue to be treated, and the diagnositic or therapeutic substance injected with a syringe through the elongated cannula and out its distal end into the tissue to be treated.
The system of the invention has the capability to access tissue in the endocardial, myocardial, and epicardial layers of the heart wall, in addition to other areas of the heart. The invention provides access to a wide region of the patient""s endocardial lining and the tissue beneath it which defines the heart chamber. The system also accurately places and effectively holds the distal end of the system at one or more desired locations within the patient""s heart chamber at a desired orientation, e.g. perpendicular or near perpendicular, with respect to the patient""s endocardium.
In another embodiment, an elongated device has a handpiece for delivering a metered dose of a substance via a delivery lumen. The elongated device may be either a catheter or an intraoperative probe, and in certain preferred embodiments has a reservoir containing the substance in a deliverable state, such as an angiogenic agent. Preferably, the device comprises a metered dispensing apparatus for injecting one or more appropriate doses and includes a dispensing control system, such as a switch disposed on the handpiece or a separate foot pedal. In some embodiments, the dispensing control system is automated, and preferably, a signal generated by the heart is provided to a circuit synchronizing the activation of the automated dispensing apparatus to the cardiac cycle. For example, the apparatus may be synchronized to the patient""s ECG by a circuit which inhibits activating the dispensing apparatus during a pre-determined portion of the cardiac cycle.
In some embodiments, the delivery device has a distal end which is configured for penetration into the patient""s tissue, e.g., has a sharp or needle-like distal end, and has at least one orifice in fluid communication with a lumen extending through the distal extremity of the device which is in fluid communication with the one or more orifices and a source of therapeutic or diagnostic substance. Additionally, in certain embodiments, the distal end has one or more radially oriented lumens to direct the substance to be delivered laterally within the patient""s tissue. Another aspect of certain embodiments of the present invention relates to contacting the tissue to be treated with the distal end. For example, elongated elements such as bristles or barbs may be provided that deploy from a first position inhibiting tissue contact to a second position permitting tissue contact are provided in some embodiments. Preferably, the elongated elements are aligned with a longitudinal axis of the device and disposed along an outside surface so they deploy from a first position that inhibits tissue engagement to a second position that permits tissue engagement. In other embodiments, the distal end can have an enlarged or bulbous section, which may or may not be expandable.
Other aspects of certain embodiments of the present invention include providing the device with a radiopaque marker disposed at the distal end to aid in the fluoroscopic visualization thereof during the procedure and providing a depth stop to limit device penetration depth. One preferred embodiment of a depth stop is the construction of a section of the distal end smaller in diameter than a second section immediately proximal of the distal section and a shoulder connecting the distal section and the second section that acts as the depth stop. Alternatively, the depth stop can be one or more mechanical elements or arms that extend out radially from the distal end. In other embodiment, visualization of the dose is accomplished by the administration of a marker substance either along with or in addition to the therapeutic substance such as an angiogenic agent. In another aspect of the present invention, multiple lumen catheters or probes are provided with one of the plurality of lumens being used to deliver the substance such as an angiogenic agent, while other lumens may be utilized to deliver other fluids, substances, or apparatus.
In certain embodiments, the present invention may also be provided with a distal tissue contact device for energy delivery to the myocardium to perform a procedure that dissects, disturbs, disrupts or ablates the tissue region to which the substance is injected. The distal tissue contact device may be one of a number of known apparatus whereby energy is delivered to the myocardium to perform a procedure that dissects, disturbs, disrupts or ablates the tissue. For example, the distal tissue contact device can be a mechanical device affixed to the distal end, or it can be a device such as a laser energy conductor, an RF energy conductor, an ultrasound transducer, or a current conductor. In another preferred embodiment, the distal tissue contact device can be a lumen in a device connected to a source of fluid at a pressure and velocity sufficient to disrupt tissue. In any of these embodiments, the distal tissue contact device is preferably introduced using a lumen separate from a lumen carrying the therapeutic or diagnostic substance to be delivered.
Thus, one preferred embodiment of the present invention broadly discloses an injector apparatus synchronized to a cardiac cycle signal that has a conduit with a least one lumen connected on a proximal end to an injection device and, preferably, a solenoid connected to the injection device. In use, a controlled amount of a substance to be delivered is dispensed when the solenoid is pulsed by a signal related to the cardiac cycle. Preferably, the solenoid advances the same amount after each of one or more pulses, so that more than one injection can be given in each heartbeat if desired. When an embodiment including a distal tissue contact device is used, an activation switch is also provided and energy is introduced into the heart tissue by operation of the activation switch, preferably but not necessarily in synchronization with the cardiac cycle.
Another additional aspect of the present invention is the provision of an apparatus for delivering a bolus of substance that has a delivery lumen extending from a distal end to a proximal point distal to the proximal end, and wherein at least a first section of the delivery lumen is filled with the substance to be delivered. In certain embodiments a second section of the delivery lumen in fluid communication with the first section is provided that contains a second substance other than the first which may aid in delivery or visualization of the first substance when it is delivered. In any embodiment, it is preferred, though not required, that the substance, i.e., an angiogenic agent, is in a fluidic or thixotropic state to facilitate delivery. In one presently preferred embodiment, the delivery lumen contains at least an angiogenic agent and a marker substance.
Although it will be readily understood that the percutaneous and intraoperative versions of the present invention may differ markedly in construction, each device may have one or more of a number of features addressed below. The discussion of these features of a substance delivery system is thus not specific to or limited to either the percutaneous or intraoperative embodiments.
As used herein, the term xe2x80x9cangiogenic agentxe2x80x9d includes any material or substance useful in a procedure that promotes the growth of new vessels, particularly the growth of new vessels in the myocardium, however, it will be understood that an angiogenic effect is useful in other organs, such as the liver and kidneys. The methods and apparatus of the present invention may employ a wide variety of angiogenic agents, including small molecule drugs, active compounds and cellular and gene therapy agents. Examples of active compounds include, by way of non-limiting example, biologically active carbohydrates, recombinant biopharmaceuticals, agents that are active in the regulation of vascular physiology, such as nitric oxide agents that effect the regulation of gene activity by modulating transcription, the turnover of cellular mRNA, or the efficiency with which specific mRNA is translated into its protein product, i.e., antisense pharmaceuticals. Other active compounds include hormones, soluble receptors, receptor ligands, peptides (both synthetic and naturally occurring), peptidomimetic compounds, specific and non-specific protease inhibitors, postaglandins, inhibitors of prostaglandin synthase and/or other enzymes involved in the regulation of prostaglandin synthesis, growth factors that affect the vascualture such as the fibroblast growth factors (FGF""s), acidic (aFGF, FGF-II) and basic fibroblast growth factors (bFGF, FGF-I), vascular endothelial growth factors (VEGF), angiogenin, transforming growth factor alpha, and transforming growth factor beta. The foregoing list is meant to illustrate the breadth of angiogenic agents and other substances useful with the present invention and is not meant to be exhaustive or in any way limit the scope of the invention. It is contemplated that there are classes of angiogenic agents possessing structures significantly similar to other molecular agents, and that these agents will have specific biological activities associated with them while being deficient in other biological activities that are less desirable therapeutically. Any and all of the angiogenic agents useful with the present invention may comprise substantially pure compounds, defined or relatively less well defined admixtures of compounds, such as those that might result from a biological system such as conditioned serum or conditioned cell culture media.
Finally, any reference to xe2x80x9cangiogenic agentxe2x80x9d herein will be understood to include diagnostic agents and markers useful with the present invention. Such diagnostic agents or markers may be delivered before, after or during the administration of the angiogenic agent itself, and include any substances used to ascertain the physical location, configuration or physiologic state of a tissue or tissues, e.g., dyes, stains, diagnostic challenge agents and agents such as radiopaque agents used to enhance contrast during diagnostic or therapeutic procedures such as myogenic compounds, anesthetic agents or chemical sypathectomy agents.